Synthesis, cytotoxic activity and quantum chemical calculations of new 7-thioxopyrazolo[1,5-f]pyrimidin-2-one derivatives

Article abstract of DOI:10.1016/j.molstruc.2019.127261

The reactions of 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives 1 and 2 with chloroacetyl chloride in the presence of sodium acetate led to the formation of 7-thioxopyrazolo [1,5-f]pyrimidin-2(1H,3H,7H)-one derivatives (3 and 4) in 78–80% yields. The s

Full text of DOI:10.1016/j.molstruc.2019.127261

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Synthesis, cytotoxic activity and quantum chemical calculations of new 7-
thioxopyrazolo[1,5-f]pyrimidin-2-one derivatives
Zülbiye Kökbudak, Murat Saracoglu, Senem Akkoç, Zeynep Çimen, M. Izzettin
Yilmazer, Fatma Kandemirli
PII:
S0022-2860(19)31370-5
DOI:
https://doi.org/10.1016/j.molstruc.2019.127261
MOLSTR 127261
Reference:
To appear in: Journal of Molecular Structure
Received Date: 13 June 2019
Revised Date: 18 October 2019
Accepted Date: 19 October 2019
Please cite this article as: Zü. Kökbudak, M. Saracoglu, S. Akkoç, Z. Çimen, M.I. Yilmazer, F.
Kandemirli, Synthesis, cytotoxic activity and quantum chemical calculations of new 7-thioxopyrazolo[1,5-
f]pyrimidin-2-one derivatives, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
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Graphical Abstract:

Synthesis, cytotoxic activity and quantum chemical calculations of new 7-
thioxopyrazolo[1,5-f]pyrimidin-2-one derivatives
Zülbiye Kökbudak 1*, Murat Saracoglu 2, Senem Akkoç 3, Zeynep Çimen 4, M. Izzettin
Yilmazer 2 and Fatma Kandemirli 5
1 Erciyes University, Faculty of Science, Department of Chemistry, 38039, Kayseri, Turkey
2 Erciyes University, Faculty of Education, 38039, Kayseri, Turkey
3 Suleyman Demirel University, Faculty of Pharmacy, Department of Basic Pharmaceutical
Sciences, 32260, Isparta, Turkey
4 Ankara Hacı Bayram Veli University, Polatlı Faculty of Science and Arts, Department of
Chemistry, 06900, Ankara, Turkey
5Kastamonu University, Faculty of Engineering and Architecture, 37150, Kastamonu, Turkey
*Corresponding author: E-mail: zulbiye@erciyes.edu.tr (Z. Kökbudak)
ABSTRACT
The reactions of 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives 1 and 2 with
chloroacetyl chloride in the presence of sodium acetate led to the formation of 7-
thioxopyrazolo[1,5-f]pyrimidin-2(1H,3H,7H)-one derivatives (3 and 4) in 78-80% yields. The
structure of these newly synthesized compounds 3 and 4 were fully characterized by 1H NMR,
13C NMR, FT-IR spectroscopies and elemental analyses. The quantum-chemical calculations
were made to find molecular properties of the 3 and 4 by using DFT/B3LYP method with 6-
311++G(2d,2p) basis set. Quantum chemical features such as HOMO, LUMO, energy gap,
ionization potential, chemical hardness, softness, electronegativity, dipole moment and etc.
values for gas and solvent phase of neutral molecules were calculated and discussed.
Furthermore, the cytotoxic activities of 3 and 4 were tested against human liver cancerous cell
line (HepG2) and human breast cancerous cell line (MDA-MB-231) for 24 h and 48 h,
respectively.
Keywords: Cytotoxic activity; DFT; Pyrimidine; Quantum chemical calculations.
1

1. Introduction
Pyrimidine and its derivatives continue to attract considerable attention due to very
wide spectrum of biological activities. Numerous pyrimidine derivatives are reported that they
exhibit antifungal [1], antiviral [2], anticancer [3], anti-inflammatory [4] and antihistaminic
[5] activities. Some pyrazole such as Celebrex [6], Viagra [7] and Acomplia [8] are
commercially available. Similarly, pyrazolopyrimidine derivatives have attracted wide
pharmaceutical interest because of their anti-trypanosomal activity [9], anti-schistosomal
activity [10], and other activities such as HMG-CoA reductase inhibitors [11], COX-2
selective inhibitors [12].
In recent years, the reactions of 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives
with anhydrides [13], 1,3-dicarbonyl compounds [14], acyl chlorides [15,16] and transition
metal complexes [17] have been reported. These interesting activities and reactions have
simulated chemists to develop the chemistry of this class of compounds.
In the present study, the key starting materials (1-amino-4-phenyl-2-thioxo-1,2-
dihydropyrimidin-5-yl)(phenyl)methanone
(1)
and
(1-amino-2-thioxo-4-p-tolyl-1,2-
dihydropyrimidin-5-yl)(p-tolyl)methanone (2) were prepared in two steps from furan-2,3-
diones and acetophenonthiosemicarbazone. These starting materials were reported in earlier
published study [19] (Scheme 1). After synthesis of 1 and 2, the new 4-benzoyl-5-phenyl-7-
thioxopyrazolo[1,5-f]pyrimidin-2(1H,3H,7H)-one (3) and 4-(4-methylbenzoyl)-7-thioxo-5-p-
tolylpyrazolo[1,5-f]pyrimidin-2(1H,3H,7H)-one (4) were prepared from the reaction of 1-
amino-2-thioxo-1,2-dihydropyrimidin derivatives (1 and 2) with chloroacetyl chloride
(Scheme 2). They were characterized by FT-IR, 1H and 13C NMR.
In addition to experimental study, optimization of molecules was performed by using
DFT/B3LYP/6-311++G(2d,2p) basis set of Gaussian 09, Revision A.02 program [20]. This
basis set is known as one of the basis sets that gives more accurate results in terms of the
determination of electronic and geometries properties for a wide range of organic compounds
[21]. The quantum chemical calculation of the molecules was carried out using density
functional theory/the integral equation formalism polarisable continuum model
(DFT/IEFPCM) [22], with basis set 6-311++G(2d,2p) for solvent phase. Quantum chemical
parameters of investigated molecules such as the energy of the highest occupied molecular
orbital (EHOMO), the energy of the lowest unoccupied molecular orbital (ELUMO), HOMO-
LUMO energy gap (ꢀE), ionization potential (I), chemical hardness (ղ ), chemical softness
2

(σ), electronegativity (χ), chemical potential (µ), dipole moment (DM), global electrophilicity
(ω) and total of negative MAC, Mulliken charges of some atoms for gas and solvent phase of
neutral molecules (3 and 4) were calculated, and the relationship between the activity and
stability of the molecules of these results was discussed. Recently, the optimization of the
molecules with different basic sets by using Gaussian program and the discussion of results
have been widely used [18, 23-25].
After completed synthesis and characterization of compounds 3 and 4, they were
tested against two cancerous cell lines for learning their cytotoxic activities.
2. Experimental Section
2.1. General materials and instruments
All necessary solvents and reagents were purchased from Merck and Sigma-Aldrich
(Chemicals Pvt Ltd.). Melting points were determined on the digital melting point apparatus
(Electrothermal 9100). The synthesized compounds were checked for their homogeneity by
TLC. Microanalyses were performed on a Leco CHNSO-932 Elemental Analyser and the
results agreed favourably with the calculated values. The IR spectra were recorded on a
Shimadzu Model 8400 FT-IR spectrophotometer. Around 3 mg of compounds were put to
FT-IR spectrophotometer device and the spectra was taken in a few minutes. The 1H and 13C
NMR spectra were recorded on a Bruker 400(100) MHz Ultra Shield instrument. The
chemical shifts are reported in ppm from tetramethylsilane as an internal standard and are
given in δ (ppm). A Hitachi UH 5300 Double Beam UV–vis Spectrophotometer (Tokyo,
Japan) was used for determining of absorbance values of compounds at 250-800 nm (λmax).
2.1.1. 4-Benzoyl-5-phenyl-7-thioxopyrazolo[1,5-f]pyrimidin-2(1H,3H,7H)-one (3)
A mixture of compound 1 (0.2 g, 0.68 mmol), sodium acetate as a base (1g, 12 mmol)
and chloroacetyl chloride (0.4 mL, 2.5 mmol) in acetonitrile (50 mL) was stirred with
magnetic stirrer at room temperature for 5 h. The solvent was evaporated. Then, the residue
was treated with dry diethyl ether. The product 3 which precipitated was filtered off, washed
several times with water and recrystallized from ethyl alcohol. Yield: 78%. M.p.: 205-207 oC.
Elemental analysis (%) for C19H13N3O2S, Found (Calc.): C= 65.51 (65.69); H= 3.62 (3.77);
N= 12.04 (12.10); S= 9.12 (9.23). FT-IR (cm-1) Found (Theo.): 3058 (3210-3172) (aromatic
C-H), 2956 (3120-3086) (aliphatic C-H), 1668 (1817) and 1650 (1696) (C=O), 1595-1475
3

(1603-1533) (C=C and C=N), 1274 (1327) (C=S), 740-660 (820-701) (pyrimidine ring
skeleton vib.). 1H NMR (ppm, found: 400 MHz, CDCl3), Found (Theo.): 8.53 (10.14) (s, 1H,
13
NH), 7.80-7.28 (8.81-7.45) (m, 10H, Ar-H), 3.62 (4.75-3.79) (s, 2H, CH2). C NMR (ppm,
100 MHz, CDCl3), Found (Theo.): 190.6, 166.4, 158.7, 156.2, 143.8, 135.0, 134.7, 133.8,
132.2, 130.0, 130.2, 129.6, 129.2, 129.0, 128.2 and 26.5 (201.6, 178.5, 171.3, 170.4, 157.3,
145.6, 144.6, 140.0, 138.1, 137.6, 137.2, 136.8, 136.7, 135.0, 134.9, 133.8, 133.4, 121.6 and
44.2).
2.1.2. 4-(4-Methylbenzoyl)-7-thioxo-5-p-tolylpyrazolo[1,5-f]pyrimidin-2(1H,3H,7H)-one (4)
A mixture of compound 2 (0.3 g, 0.89 mmol), sodium acetate as a base (1g, 12 mmol)
and chloroacetyl chloride (0.3 mL, 3.76 mmol) in acetonitrile (50 mL) was stirred by a
magnetic stirrer at room temperature for 24 h. The solvent was evaporated. Then, the residue
was treated with dry diethyl ether. The product 4, which precipitated, was filtered off and
o
recrystallized from ethyl alcohol. Yield: 80%. M.p.: 214-216 C. Elemental analysis (%) for
C21H17N3O2S, Found (Calc.): C= 66.97 (67.18); H= 4.59 (4.56); N= 11.34 (11.19); S= 8.41
(8.54). FT-IR (cm-1) Found (Theo.): 3066 (3206-3168) (aromatic C-H), 2964 (3114-3112)
(aliphatic C-H), 1664 (1815) and 1644 (1637) (C=O), 1595-1569 (1611-1524) (C=C and
C=N), 1271 (1328) (C=S), 740-660 (810-717) (pyrimidine ring skeleton vib.). 1H NMR (ppm,
found: 400 MHz, CDCl3), Found (Theo.): 8.43 (10.14) (s, 1H, NH), 7.72-7.14 (8.67-7.18) (m,
8H, Ar-H), 3.60 (4.73-3.75) (s, 2H, CH2), 2.42 and 2.33 (2.74-2.19) (s, 6H, 2CH3). 13C NMR
(ppm, 100 MHz, CDCl3), Found (Theo.): 190.3, 166.7, 158.6, 155.9, 146.5, 143.6, 143.2,
132.3, 131.0, 130.2, 129.9, 129.8, 129.6, 128.1, 26.6, 21.9 and 21.6 (201.0, 178.3, 171.6,
169.4, 156.0, 153.5, 150.8, 142.8, 141.8, 137.8, 136.7, 136.4, 135.6, 135.5, 134.5, 133.9,
122.4, 44.2, 24.1 and 24.0).
2.2. Computational details
Molecular properties, related to the reactivity and selectivity of the compounds, were
estimated following the Koopmans’s theorem relating the energy of the HOMO and the
LUMO. According to the DFT-Koopmans’ theorem [26, 27], the ionization potential (I) can
be approximated as the negative value of EHOMO, such as shown in equation 1:
I = −EHOMO
(1)
The negative value of ELUMO is similarly related to the electron affinity (A) [28] such as
4

shown in equation 2:
A = −ELUMO
(2)
Energy gap (∆E) is estimated by using EHOMO and ELUMO
∆E = ELUMO −EHOMO (3)
Electronegativity (χ) is estimated using following the equation 4 from I and A [29, 30]:
:
I + A


χ =
(4)




2
The chemical hardness (η) measures the resistance of an atom to a charge transfer [29],
it’s estimated by using the equation from I and A [30] or EHOMO and ELUMO
5
:
I − A
E
LUMO − E

 
 


HOMO 
η =
=
(5)


 
2
2
The electron polarizability is called chemical softness (σ), describes the capacity of an
atom or group of atoms to receive electrons [29] and it is estimated from chemical hardness or
EHOMO and ELUMO by using the equation 6:


1
2




σ =
−
(6)
η
EHOMO −ELUMO


The chemical potential (µ) and electronegativity (χ) can be calculated with the help of
the following equations [21] from EHOMO and ELUMO
:
E
+ELUMO




HOMO
µ = −χ
(7)
2


The global electrophilicity index (ω) is a useful reactivity descriptor that can be used to
compare the electron-donating abilities of molecules [31]. A high value of electrophilicity
describes a good electrophile while a small value of electrophilicity describes a good
nucleophile [32]. ω is estimated by using the electronegativity and chemical hardness
parameters through the equation:
χ2
ω =
(8)
2η
5

2.3. Cytotoxic activity study
Cytotoxic activity studies were conducted according to published literature procedure
[33-35]. MDA-MB-231 and HepG2 were cultured in DMEM medium supplemented with 1%
Glutamax and 10% FBS. The cancerous cells were seeded into sterile 96-well plates at a
density of 4 x 103 cells/well. These plates were placed in an incubator. After 24 h incubation
time, seeding cells were exposed to synthesized drug candidates 3 and 4 at six different
concentrations following 5, 10, 20, 50, 100 and 200 µM. Then, plates were again incubated
for 24 h (for HepG2) or 48 h (for MDA-MB-231). In the following step, MTT stock solution
(50 µL, 5 mg/mL) was put to each well and was incubated for 3 h. After the time completed,
medium was replaced with 200 µL of DMSO. Using Promega reader device, the absorbance
values were measured at 560 nm. IC50 values were calculated with GraphPad Prism 7 software
program.
3. Results and Discussion
3.1. Structural analysis
The 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives 1 and 2 were synthesized
according to the reported literature procedure [12] as shown in Scheme 1 [19].
Scheme 1. Synthesis of 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives (1 and 2).
6

Two new 7-thioxopyrazolo[1,5-f]pyrimidin-2(1H,3H,7H)-one derivatives (3 and 4)
were prepared in excellent yields (78 and 80%) from the reaction of chloroacetyl chloride
with 1, 2 compounds in the presence of a catalytic amount of sodium acetate (Scheme 2). The
1
structures of the new compounds 3 and 4 were characterized using elemental analysis, H
13
NMR, C NMR and FT-IR spectroscopic techniques (for details see Experimental Section).
The proposed mechanism for the formation of 3 and 4 is depicted in Scheme 3.
Scheme 2. Synthetic scheme for the compounds 3 and 4.
Chloroacetyl chloride is active compound that is often used as a two-carbon building
block reagent given its multi-functional properties [36]. The reaction is initiated by the
nucleophilic attack of the nitrogen atoms of 1, 2 directed to carbonyl’s group of chloroacetyl
chloride. At the first step, chloroacetamide derivatives occur by the nucleophilic acyl
substitution of 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives. At the last step,
chloroacetamide derivatives go through a rearrangement to yield novel heterocyclic
compounds 3, 4 via intramolecular cyclization reaction takes place to give new five-
membered part of compounds 3, 4 called as a pyrazole ring.
Compound 3 was obtained in 78% yield by treating chloroacetyl chloride with 1 in
acetonitrile at room temperature for 5 h. The structure of the compound 3 was confirmed by
its analytical and spectral data. When the IR spectra of compounds 3, 4 were compared with
that of the compounds 1 and 2, the absence of NH2 around at 3350-3250 cm-1 verify the
structure of compounds 3 and 4. NH- tensile vibrations of aromatic primary amines were
observed at around 3350-3250 cm-1 [19]. A characteristic stretching absorption band was
obtained at 3060 cm-1 for pyrimidine ring of compound 3. In the IR spectrum of compound 3,
7

the two C=O and C=S absorption bands were found (theo.) to be at 1650 (1696) (for C=O in
benzoyl group), 1668 (1817) (for C=O in pyrazole ring) and 1274 (1327) (for C=S) cm-1.
1H NMR spectrum of compound 3 showed signals at δ 7.80-7.28 (8.81-7.45) ppm for
aromatic protons. The peak at δ 8.53 (10.14) ppm represented the -NH. In the 13C NMR
spectrum of compound 3, the peaks corresponding to δ 190.6 (201.6) and 26.5 (44.2) ppm
indicated the presence of carbonyl (C=O) and methylene (CH2) groups, respectively.
Scheme 3. Proposed mechanistic path for the synthesis of compounds (3, 4).
The reaction of compound 2 with chloroacetyl chloride leads to form compound 4.
The IR spectrum of 4 exhibited stretching frequencies at 3066 (3206-3168) and 2964 (3114-
3112) (for the aromatic C-H, aliphatic C-H), 1664 (1815) and 1644 (1637) cm−1 (for the two
C=O groups). In addition, the presence of absorption band corresponding thiocarbonyl (C=S)
8

1
was observed as found (theo.) at 1271 (1328) cm−1. Its H NMR spectrum displayed four
singlet signals at δ 8.43 (10.14), 3.60 (4.73-3.75), 2.42 and 2.33 (2.74-2.19) ppm due to NH,
CH2 and two CH3 protons, respectively. Aromatic protons were observed in the region δ 7.72-
7.14 (8.67-7.18) ppm as multiplet. 13C NMR spectrum of 4 showed signals at δ 190.3 (201.0)
ppm which was assigned to ph-C=O. The signals for methylene and methyl carbons were
observed at δ 26.6 (44.2), 21.9 (24.1) and 21.6 (24.0) ppm. The other carbons were observed
in the region of δ 166.7 (178.3)-128.1 (122.4) ppm.
3.2. Absorption spectroscopy study
The absorption spectra of the compounds were recorded in DMSO and are shown in
Fig. 1.
0.8
0.6
3
4
0.4
0.2
0
220 235 250 265 280 295 310 325 340 355 370 385 400 415 430
-0.2
-0.4
-0.6
Wavelength, nm
Fig. 1. UV-Vis absorbance spectra of compounds.
The maximum UV-Vis absorption spectra result for compounds 3 and 4 were screened
from 200 to 800 nm. The absorption spectra were computed using the TDDFT method in
combination with the same functional, basis set in gas phase. The calculated maximum
absorption wavelengths (λmax), and electronic transitions are shown in Table 1. The highest
absorption values were obtained at 275 and 400 nm for compound 3, and 280 and 400 nm for
compound 4 as experimental, and the highest absorption values were calculated at 290 and
386 nm for compound 3, and at 294 and 383 nm for compound 4. It was found that the intense
9

band at 290 nm can be considered HOMO-3 → LUMO, HOMO-3 → LUMO+1, HOMO-2 →
LUMO, HOMO-1 → LUMO+2, HOMO → LUMO+2 translations for compound 3 and the
translations at 294 were composed of HOMO-1 → LUMO, HOMO → LUMO, HOMO →
LUMO+1, HOMO → LUMO+2 for compound 4.
Table 1
Theoretical UV-Vis absorbance spectra of compounds.
Compounds
Electronic Transitions
Electronic Transitions
λmax
λmax
3
290
386
HOMO-3 → LUMO
HOMO-3 → LUMO+1
HOMO-2 → LUMO
HOMO-1 → LUMO+2
HOMO → LUMO+2
HOMO-5 → LUMO
HOMO-4 → LUMO
HOMO-3 → LUMO+1
HOMO-1 → LUMO+2
HOMO-1 → LUMO
HOMO → LUMO
HOMO → LUMO+1
HOMO → LUMO+2
4
294
383
HOMO-1 → LUMO
HOMO → LUMO
HOMO → LUMO+1
HOMO → LUMO+2
3.3. Molecular structure
The EHOMO, ELUMO, ∆E, I, η, σ, χ, etc. values were calculated for 3 and 4 with the
DFT/B3LYP/6-311++G(2d,2p) method for gas and ethanol phase of neutral molecules, as
shown in Figs 2-5, and Tables 2 and 3.
The HOMO and LUMO are known as frontier orbitals, and these molecules play
important role in the determination of their molecular reactivity or stability. Some researchers
mention that frontier molecular orbital (FMO) theory is useful in predicting interaction center
of molecule [37]. The FMOs of the molecules 3 and 4 are given in Fig. 2. It could be easily
found that the HOMO distributions of 3 and 4 compounds are mainly located around of
pyrimidine ring, amine group and sulphur for gas and solvent phase of neutral molecules. Fig.
10

2 shows that the HOMO distributions for gas and solvent phase of the compounds 3 and 4 are
approximately in the same regions. The electron-rich regions of the molecule can be said to be
more active. The presence of nitrogen, oxygen and sulphur atoms on these molecules are
cause to be strong activity. This figure shows that there is much more electron density in
nitrogen, oxygen and sulphur atoms of 3 and 4 for both phases. The results show that the
molecules are easier to interact with these bound atoms. It can be seen from Fig. 2 that the
LUMO distributions of the molecules for gas and solvent phase are similar for molecules 3
and 4. The LUMO distributions of 3 and 4 are mainly located around of all molecules.
According to the FMO, the chemical reactivity of molecule is a function of interaction
between HOMO and LUMO levels of the reacting species.
3-LUMO
4-LUMO
3-HOMO
3*-LUMO
4*-LUMO
3*-HOMO
11

4-HOMO
4*-HOMO
Fig. 2. Frontier MOs (HOMOs, LUMOs) molecules by using DFT/B3LYP/6-311++G(2d,2p)
basic set for gas and ethanol (*) phase.
EHOMO and ELUMO are associated with electron donating and electron accepting ability
of a molecule, respectively. High EHOMO is essential for reaction with nucleophiles of
molecule while low ELUMO is essential for reaction with electrophiles [38]. EHOMO values were
found as -6.34, -6.24 eV for gas phase, and -6.50, -6.46 eV for solvent phase for 3 and 4,
respectively (Fig. 3). According to these results, molecule 3 was found to be more reactive
than the other molecule 4 for gas and solvent phase. EHOMO values in molecule 3 is higher
than the other molecule. This is due to the methyl group attached to the phenyl ring. The
methyl group is an electron donor group.
12

Fig. 3. Calculated HOMO, LUMO and energy gap (∆E) parameters for gas and solvent (*:
ethanol) phase of neutral molecules using B3LYP/6-311++G(2d,2p) method.
HOMO-LUMO energy gap (∆E, see eq. 3), chemical hardness and softness are closely
related to chemical properties [39, 40]. The physical properties of the compounds are strongly
dependent on ∆E values. The large ∆E indicates a high kinetic stability and also low
molecular activity of the compound. Because it is more difficult for molecules with high ∆E
values to be polarized. The compounds need more energy to excite but lower gaps of the
energy are relatively easy to polarize and it reacts more efficiently than higher values of the
energy gaps [41]. Pearson showed that hard molecules with a high ∆E values are more stable
compared to soft molecules with a low ∆E values [42]. The smaller ∆E is often interpreted by
a stronger activity and perhaps greater inhibition efficiency [43]. So, ꢀE decreases, the
reactivity of the molecule increases leading to a better inhibition efficiency and activity [40].
∆E values were found as 3.60, 3.82 eV in gas phase and 3.63, 3.84 eV in solvent phase for 3
and 4, respectively. ∆E values in the gas phase are lower than the solvent phase. Therefore,
the gas phase is expected to be more active than solvent phase. This is due to the dielectric
coefficient of the solvent. In this case, molecule 3 is found more active than molecule 4 for
both phases due to the fact that a low ∆E value is observed (Fig. 3).
13

The ionization potential (I) is one of the fundamental indicators of the chemical
reactivity. High values of the ionization potential (Eq. 1) evidence the chemical inertness and
strong stability, whereas small ionization potential denotes high activity of the atoms and
molecules [44]. According to ionization potential values, order of activity can be written as: 4
(6.24 eV) < 3 (6.34 eV) for gas phase, and 4 (6.46 eV) < 3 (6.50 eV) for solvent phase (Fig.
4). As in ∆E values, in the gas phase I values are lower than the solvent phase for 3 and 4.
Molecule 4 is found more active than molecule 3 for gas and solvent phase. Because,
molecule 4 has the lowest ionization potential value. It can be seen from the results that the
stable for gas and water phase belongs to molecule 3 (Fig. 4).
Chemical hardness introduced in 1960s by Pearson is defined as the resistance towards
electron cloud polarization or deformation of chemical species [38]. According to the
Maximum Hardness Principle states; “a chemical system tends to arrange itself so as to
achieve maximum hardness and chemical hardness can be considered as a measurement of
stability”. The hardness (η) and softness (σ) are widely used in chemistry for explaining
stability of compounds. According to Maximum Hardness Principle, chemical hardness is a
measure of the stability of chemical species. The hardness is just half the energy gap between
the EHOMO and ELUMO (see eq. 5). If a molecule has a large energy gap, it is called hard and
otherwise is called soft [42]. The active compounds have a greater softness value. Softness
(see eq. 6) is a measure of the polarizability and soft molecules give more easily electrons to
an electron acceptor molecule or surface [21]. The calculated chemical hardness and softness
values are given in Fig. 4. According to softness values, electron donating trend of studied
chemical compounds may be written as 3 is more than 4 for gas and solvent phase. The
softness values for gas phase were found as 0.55, 0.55 eV, and 0.52, 0.52 eV in solvent phase
for molecules 3 and 4, respectively.
14

Ionization Potential
6-311++G(2d,2p)
6-311++G(2d,2p) Solvent
Hardness
7.00
6.00
5.00
4.00
3.00
2.00
1.00
0.00
6-311++G(2d,2p)
6-311++G(2d,2p) Solvent
2.00
1.50
1.00
0.50
0.00
3
4
3
4
Compounds
Compounds
Electronegativity
Softness
6-311++G(2d,2p)
6-311++G(2d,2p) Solvent
6-311++G(2d,2p)
6-311++G(2d,2p) Solvent
0.60
0.50
0.40
0.30
0.20
0.10
0.00
5.00
4.00
3.00
2.00
1.00
0.00
3
4
3
4
Compounds
Compounds
Fig. 4. Calculated some quantum chemical parameters for gas and solvent phase using
B3LYP/6-311++G(2d,2p) method (solvent: ethanol).
The average values of the HOMO and LUMO energies have been defined as the
chemical potential (µ). The negative value of the chemical potential was known as the
electronegativity (χ) (see eq. 4). Chemical potential, electronegativity and hardness are
descriptors for the predictions about chemical properties of the molecules [45]. The
electronegativity also indicates the propensity of an inhibitor molecule to accept electrons or
electron density. Electronegativity that represents the power to attract the electrons of
chemical species is a useful quantity in the prediction of activity of the molecules [21]. In
generally, a molecule with lower electronegativity is associated with higher electron donating
tendency and therefore exhibited higher activity as compare to a molecular with higher value
of electronegativity. The χ values were found as 4.54, 4.42 eV for gas phase and 4.59, 4.54
15

eV for solvent phase of 3 and 4, respectively. According to the electronegativity values,
molecule 3 was found to be more active than molecule 4 for both phases (see Fig. 4).
The dipole moment (DM) is another indicator of activity of chemical compounds.
Although some authors reported that there is no remarkable relationship between dipole
moment and inhibition efficiency and some authors showed that activity increases with the
increasing of the dipole moment [46-48]. In some studies, authors supported that increasing
value of dipole moment facilitates the electron transport process [47, 48]. For instance, DM
values found are 6.99, 8.25 Debye in gas phase and 9.83, 11.46 Debye in solvent phase for 3
and 4, respectively (Table 2). According to DM results, molecule 4 was found to be more
active than compound 3 for gas and solvent phase.
Table 2
The calculated some quantum chemical parameters for gas and solvent phase of the neutral
compounds using B3LYP/6-311++G(2d,2p) method.
Molecule
µ, eV
-4.54
-4.42
-4.59
-4.54
DM, Debye
MV, cm3/mol
TMAC, e
ω, eV
5.70
5.37
5.51
5.35
3
6.99
208.86
-4.38
4
8.25
266.72
-5.41
3*
9.83
267.98
-4.94
4*
11.46
268.00
-5.85
*Solvent phase: ethanol
The total of negative Mulliken atomic charges (TMAC) can be seen from Table 2.
The TMAC values have been found as: -4.38 eV (for 3), -5.41 eV (for 4) in gas phase and -
4.94 eV (for 3), -5.85 eV (for 4) in solvent phase. According to DM results, compound 4 was
found as active molecule for both phases. The negative charge densities have been shown to
increase on active molecules. The results of other calculations: global electrophilicity index
(ω) and MV can be seen in Table 2.
DFT study can be used to better understand the molecular behaviour and structural
conformation of the compounds. DFT approach helps to study the electrostatic potential
(ESP) distribution of the compound more precisely [41]. Molecular Electrostatic Potential
(MEP) is used to describe the electrostatic interaction between a molecule and an atom. ESP
is indicating the electrophilic and nucleophilic nature of the molecules, and its essential tools
to study the reactivity nature of the compounds. MEP maps at the surface are represented by
16

different colours. The blue colour in the ESP graphs, represents the maximum amount of the
positive region where the nucleophilic reaction takes place and reddish region represented the
negative region where the electrophilic reaction takes place [41], and green colour represents
zero potential. ESP surfaces of investigation compounds are shown in Fig. 5.
3
4
3*
4*
← Elec. rich
Elec. poor →
Fig. 5. Molecular electrostatic potential (MEP) surface of molecules by using DFT/B3LYP/6-
311++G(2d,2p) basic set for gas and ethanol (*) phase.
Fig. 5 shows that the electron density increases around the sulphur and oxygen atoms
with the negative electrostatic potential values of the molecules for gas and solvent phase.
Especially, most of the electrophilic reactions takes place of sulphur (9S), carbonyl oxygen
(11O) of the pyrimidine ring and O25/26O oxygen atoms for both phase of compounds 3 and
4, and the red coloured region in Fig. 5 shows that the maximum electronegativity (the
numbers of sulphur and oxygen atoms can be seen from the figure in Table 3). This result
17

indicates that these atoms will enter the electrophilic reactions more easily. On the other hand,
it can be seen that the electron density decreases around 7N atom with the positive
electrostatic potential values of the compounds.
In such studies, electronic charge analysis for atoms in the molecules is important
because the binding capability of a molecule depends also on electronic charge on
heteroatoms of the molecule. The binding facilitates as negative charge on heteroatom
increases [49]. In this study, we used Mulliken population analysis to calculate the atomic
charges. The Mulliken atomic charges on sulphur, nitrogen and oxygen of compounds 3 and 4
for non-protonated gas and solvent phases are given in Table 3.
Table 3
Calculated Mulliken atomic charges (e) on sulphur, nitrogen and oxygen atoms of compounds
3 and 4 by using B3LYP/6-311++G(2d,2p) basic set.
3
4
Atoms
3
4
3*
4*
7N
0.400
-0.449
-0.656
-0.101
-0.450
-0.405
0.400
-0.459
-0.672
-0.091
-0.451
-0.406
0.449
0.453
-0.461
-0.791
-0.168
-0.532
-0.456
8N
-0.452
-0.774
-0.170
-0.530
-0.448
9S
10N
11O
25O/26O
*Solvent phase: ethanol
In the ESP graphs (Fig. 5), the sulphur, nitrogen and oxygen atoms rich in electrons
can been seen to have higher Mulliken charges. As can be seen from Table 3, the negative
charge densities are more on 8N, 9S, O11 and 25O/26O number atoms. It is easier to bind a
molecule from these atoms where the negative value is higher. It is seen that the negative
charge values on these atoms are higher than 3 in molecule 4. The Mulliken negative charges
18

values are generally lower in gas phase than in solvent phase. As a result, these atoms in the
molecules cause to be strong interaction. This binding is expected to be stronger in molecule
4.
3.4. Cytotoxic activity studies of compounds
Synthesized compounds 3 and 4 were screened towards MDA-MB-231 and HepG2
cell lines for 24/48 h. The IC50 values calculated are given in Table 4.
Table 4
IC50 results for synthesized compounds against MDA-MB-231and HepG2 cell lines.
Compounds
IC50, µM
HepG2
215.0
167.9
139.1
MDA-MB-231
152.30
3
4
56.86
Cisplatin
N.T.*
N.T.* Not tested
When compounds (3 and 4) and positive control drug were screened in HepG2 cell
line for 24 h, IC50 values were obtained as ˃200, 167.9 and 139.1 µM for 3, 4 and cisplatin,
respectively. In here, we saw the significance of the structure activity relationship. Because,
when -CH3 was chosen instead of -H as -R group, higher cytotoxic activity result was
obtained in liver cell line. Furthermore, compound 4 containing -CH3 group showed a value
close to the IC50 result of cisplatin, a well known clinical drug, in this cell line. According to
EHOMO, I, DM and TMAC results, molecule 4 was found to be more active than molecule 3.
This result also appears to be consistent with experimental cytotoxic activity values.
19

100
90
80
70
60
50
40
30
20
10
0
3
4
5
10
20
50
100
200
Concentration, µM
Fig. 6. Cell viability ratios of MDA-MB-231 depending on concentrations of molecules 3 and
4.
Compounds 3 and 4 were also tested in MDA-MB-231 cell line for 48 h. It was found
that they had activity in the breast cancerous cell line with following IC50 values; 152.30 and
56.86 µM for 3 and 4, respectively. Compound 4 has a more toxic effect on MDA-MB-231
than 3, too. Cell viability rates varied depending on the concentrations of the compounds
tested. Cell viability at low concentrations is close to 100%, but it is seen from the figures 6
and 7 that this ratio decreases when high concentrations are reached.
100
90
80
70
60
50
40
3
4
30
20
10
0
5
10
20
50
100
200
Concentration, µM
Fig. 7. Cell viability ratios of HepG2 depending on concentrations of molecules 3 and 4.
20

4. Conclusions
As conclusion, starting from 1-amino-2-thioxo-1,2-dihydropyrimidin derivatives 1 and
2, we successfully synthesized two derivatives of 7-thioxopyrazolo[1,5-f]pyrimidin-
2(1H,3H,7H)-one (3, 4). Both experimental techniques and theoretical methods were used to
determine the structural and spectroscopic properties of these newly synthesized compounds.
1
13
The structures of compounds were completely verified using H NMR, C NMR, elemental
analysis and IR. For example; characteristic proton signal of N-H was obtained as singlet at δ
8.53 and 8.43 pmm for 3 and 4, respectively. Methyl protons (-CH3) at para positions of phenyl
and benzoyl groups in the structure of compound 4 were seen as singlet signal at δ 2.42 and 2.33
13
ppm. In the C NMR spectra, carbonyl (C=O) signals belongs to benzoyl group were found to
be resonated in the lowest area and obtained at 190.6 and 190.3 ppm for 3 and 4, respectively.
The quantum chemical parameters of 3 and 4 were calculated and discussed. According to
EHOMO, I, DM and TMAC results, the molecule 4 was found to be more active than the
molecule 3 for the gas and solvent phases of neutral compounds. Furthermore, the cytotoxic
activity studies of these molecules were done and molecule 4 was found to be more active
than 3 against two cancerous cell lines. It can be said that the cytotoxic activity results are
consistent with the quantum chemical results.
Conflict of interest
The authors have no conflict of interest to declare.
Supporting Information
Supplementary data can be found in the online version.
Acknowledgements
This study was financially supported by Erciyes University Research Fund (FBY-12-
4048) and the computers allocated by Erciyes University data center were used for quantum
chemical calculations.
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26

Highlights:
•
•
New compounds including pyrimidin nucleus were synthesized and characterized.
Quantum-chemical calculations were made for finding molecular properties of these
compounds.
•
Cytotoxic activities of compounds were tested against HepG2 and MDA-MB-231 cell
lines. Compound 4 gave higher anticancer activity than 3.

Declaration of interests
X The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: